The peripheral olfactory system has a remarkable capacity for repair after injury, and the maintenance of that capacity depends on the persistence of neurocompetent stem cells. If the stem cells are destroyed, the injured tissue undergoes respiratory metaplasia, which is a major cause of sensory dysfunction in humans. Despite the importance attached to understanding the regulation of olfactory stem cells, there is much that is not yet known, starting with their identity. Work during the previous period of support demonstrated that among the population of globose basal cells (GBCs) are cells that have many of the characteristics of stem cells, including the potency to differentiate into all the constituent cell types and the existence of slowly cycling, label-retaining cells (a hallmark of stem cells in other tissues). The 3 Specific Aims proposed in this application will provide a more in depth understanding of olfactory stem cells and how they are regulated. Aim 1 will use a transplantation/colony forming unit assay to determine the differentiate and generative capability of different marker-defined subsets of GBCs, including label-retaining ones. Aim 2 will test whether expression of members of the bHLH transcription factor family signify (and might drive) irreversible commitment to a single lineage. Aim 3 will test whether the Notch-Hes signal transduction pathway controls the choice point between neurons vs. non-neuronal cells that is made by the multipotent GBCs as they differentiate. Successful completion of the Aims will advance our understanding of olfactory stem cells and hasten their potential use as a therapeutic modality.